Several propargylamine derivatives have been shown to selectively inhibit monoamine oxidase (MAO)-B and/or MAO-A activity, which inactivate monoaminergic neurotransmitters such as dopamine, and thus to be suitable for treatment of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD), in which dopamine levels are low. These compounds have further been shown to protect against neurodegeneration by preventing apoptosis.
The first compound found to selectively inhibit MAO-B was R-(−)—N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, also known as L-(−)-deprenyl, R-(−)-deprenyl, or selegiline. In addition to PD, other diseases and conditions for which selegiline was disclosed as being useful include drug withdrawal (WO 92/21333, including withdrawal from psychostimulants, opiates, narcotics, and barbiturates); depression (U.S. Pat. No. 4,861,800); AD; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing's disease in humans and nonhumans (U.S. Pat. No. 5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); schizophrenia (U.S. Pat. No. 5,151,419); and various neoplastic conditions including cancers, such as mammary and pituitary cancers. WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative diseases and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied (see, e.g., Tatton, 1993; and Tatton and Greenwood, 1991). U.S. Pat. No. 6,562,365 discloses the use of desmethylselegiline for selegiline-responsive diseases and conditions.
Rasagiline, R(+)—N-propargyl-1-aminoindan, a highly potent selective irreversible MAO-B inhibitor, has been approved for treatment of PD in Europe, Israel, and in the U.S., under the name AZILECT® or AGILECT® (Teva Pharmaceutical Industries Ltd., Petach Tikvah, Israel). Rasagiline has been shown to exhibit neuroprotective activity and antiapoptotic effects against a variety of insults in cell cultures and in vivo (Youdim and Weinstock, 2002a). The mechanism underlying the neuroprotection by rasagiline has been studied in dopaminergic SH-SY5Y and PC12 cells in culture against apoptosis induced by N-methyl (R) salsolinol, the peroxynitrite donor N-morpholino-sydnonimine (SIN-1), 6-hydroxydopamine, and serum and nerve growth factor withdrawn (Youdim et al., 2001b; Akao et al., 1999, 2002; Maruyama et al., 2001a, 2001b, 2002).
Rasagiline and pharmaceutically acceptable salts thereof were first disclosed in U.S. Pat. Nos. 5,387,612, 5,453,446, 5,457,133, 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 as useful for the treatment of PD, memory disorders, dementia of the Alzheimer type, depression, and the hyperactive syndrome. The 4-fluoro-, 5-fluoro- and 6-fluoro-N-propargyl-1-aminoindan derivatives were disclosed in U.S. Pat. No. 5,486,541 for the same purposes. U.S. Pat. Nos. 5,519,061, 5,532,415, 5,599,991, 5,744,500, 6,277,886, 6,316,504, 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 disclose rasagiline and pharmaceutically acceptable salts thereof as useful for treatment of additional indications, in particular, an affective illness, a neurological hypoxia or anoxia, neurodegenerative diseases, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
U.S. Pat. No. 6,251,938 describes N-propargyl-phenylethylamine compounds, and U.S. Pat. Nos. 6,303,650, 6,462,222 and 6,538,025 describe N-propargyl-1-aminoindan and N-propargyl-1-aminotetralin compounds as being useful for treatment of depression, attention deficit disorder, attention deficit and hyperactivity disorder, Tourette's syndrome, AD and other dementia such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
Previous work has suggested that rasagiline and related propargylamine derivatives suppress apoptotic death cascade initiating in the mitochondria, by preventing pre-apoptotic decline in mitochondrial membrane potential (ATM) due to permeability transition and the activation of caspase 3, nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase, and nucleosomal DNA fragmentation apoptotic processes (Youdim and Weinstock, 2002b). In controlled monotherapy and as an adjunct to L-dopa, rasagiline has shown anti-Parkinson activity.
Two rasagiline analogs containing a carbamate moiety have been synthesized in an attempt to combine the MAO inhibitory and neuroprotective properties of rasagiline with the cholinesterase (ChE)-inhibiting activity of rivastigmine, a drug with proven efficacy in AD patients. These analogs are (N-propargyl-(3R)aminoindan-5-yl)-ethylmethyl carbamate (TV3326), which possesses both ChE and MAO-A and B inhibitory activities, and its S-isomer, TV3279, an inhibitor of ChE but not of MAO (Weinstock, 1999; Grossberg and Desai, 2001). Similar to rasagiline, TV3326 and TV3279 possess neuroprotective properties against a variety of insults, which are independent of the ChE and MAO inhibitory activities, but may derive from some intrinsic pharmacological activity of the propargylamine moiety (Youdim and Weinstock, 2002a). In addition, these compounds stimulate the release of the neurotrophic/neuroprotective nonamyloidogenic-soluble amyloid precursor protein (sAPPI3) via activation of the protein kinase C and mitogen-activated protein kinase pathways (Yogev-Falach, 2002). Thus, these drugs may affect the formation of potentially amyloidogenic derivatives and could be of clinical importance for treatment of AD.
U.S. Pat. No. 5,169,868, U.S. Pat. No. 5,840,979 and U.S. Pat. No. 6,251,950 disclose aliphatic propargylamines as selective MAO-B inhibitors, neuroprotective and cellular rescue agents. The lead compound, (R)—N-(2-heptyl)methyl-propargylamine, has been shown to be a potent MAO-B inhibitor and antiapoptotic agent (Durden et al., 2000).
Propargylamine was reported many years ago to be a mechanism-based inhibitor of the copper-containing bovine plasma amine oxidase (BPAO), though the potency was modest. U.S. Pat. No. 6,395,780 discloses propargylamine as a weak glycine-cleavage system inhibitor.